High-level discussion of polysubstance abuse; focus on prescription and OTC drug misuse

Professor Fabrizio Schifano, MD, FRCPsychSpecial thanks to Damicom srl; A Vento, MD. PhD; L Orsolini, MD

Psychopharmacology, Drug Misuse and Novel PsychoactiveSubstances Research Unit, University of Hertfordshire,Hatfield, Herts, UK.

Jünger (1970).Introduces the word‘Psychonaut’ todescribe individualswho tookpsychoactive drugswith the intention ofachieving greaterknowledge of what hecalled the ‘inneruniverse’,‘Psychocosmos’.

P.J. Carroll (1987) describes inhis book ‘Psychonaut’, theexperimental use of meditation,rituals and DRUGS as tools toreach the state of ‘psychonaut’in the exploration ofconsciousness.

DEFINITION AND ORIGIN OF THE TERM

PSYCHONAUTS and e-PSYCHONAUTS: self-appointed shamans?

TYPOLOGY

The ‘Chemicals’ experimenters”: who test the chemicals in order to document thedrug’s effects and to assess whether it is safe forothers to use. These subjects perceive themselvesas doing it in the name of “psychedelic research”.

The ‘Navigators of the mind”: who use drugs in order to explore the frontiers of the mind in the name of “psychonautism” as means to spiritual, interpersonal and psychological revelations.

E-PSYCHONAUTS’ FEATURES

A number of recent clinical referrals mentioning misuse of OTC and/or prescribing drugs….1.Opiates/opioids (tramadol; oxycodone; novel synth opioids)2.Designer/exotic BDZ from the web; Z-drugs; GABA-B drugs (baclofen;

phenibut)3. Gabapentinoids4. Anticholinergics; Antipsychotics5.Antidepressants 6.Ketamine; esketamine7.Anti asthmatics; clenbuterol8.OTC (loperamide; dextromethorphan; codeine;

antihistamines/promethazine)

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Fabrizio Schifano, Flavia Napoletano, Davide Arillotta, Caroline Zangani, Valeria Catalani, John Martin Corkery, Amira Guirguis, Deja Berritta, Liam Gilgar, Alessandro Vento

NPS FINDER

NPS.Finder® is a Damicom/Rome basedcrawling/navigating software, designed toautomatically scan a 9-language range ofpsychonaut web sites/fora fornew/novel/emerging molecules.

eg. Bluelight, Erowid, isomerdesign, etc.

After about 27 months of web crawler activities,the number of substances identified is >6,000;

of these, 4,335 unique molecules have beenincluded in the database and about 1,700 (29%)of the remaining molecules resulted to be falsepositives duplicates.

Most popular molecules:

• Psychedelic phenethyllamines (around 30%)

• Synthetic cannabimimetics (around 30%)

• Novel synthetic opioids (around 11%)

Current findings; n=4,335 NPS identified

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Number of molecules

• 179 PIA/phenethylamines/MDMA-like drugs; amphet-type substances (fluoroamphetamine, PMA, 2C-T, 2C-B etc);

• PIA derivatives: ‘fly’; NBOMe; indanes; benzofurans (5; 6-APB/APDB; EAPB); ‘BenzoFury’

• lysergamides such as LSA, 1P-LSD, ALD-52, ETH-LAD, Pro-LAD, AL-LAD, LSZ and LSD-like structures• Up to 700 synthetic cannabimimetics; incl: BB-22; FPB-22; AKB-48F; AM-2201; AM-2233; • >100 synthetic cathinones; incl: mephedrone; methedrone; methylone; alpha-PVP etc

• Novel stimulants; aminorex derivatives; 4,4’-DMAR• Synthetic opiates/opioids, such as >20 fentanyls (e.g. carfentanil); AH-7921; IC-26; MT-45;

nortilidine; W15; W18; U-47700, U-48800, U-51,754 • synthetic cocaine substitutes: RTI 111; RTI 121; RTI 126; ‘fake’ cocaine/gogaine

(lidocaine+MPA+ephedrine); ‘el blanco’ (ethylphenidate and benzocaine)

Schifano, Orsolini et al. 2015; Schifano, 2015; Schifano, Orsolini et al., 2016; Schifano et al., 2016; Chiappini and Schifano, 2019; Schifano et al, 2020)

…the few thousands of different NPS currently available… (part 1)

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• 64 tryptamine classical derivatives and 5 tryptamine derivatives such as 5-Meo-DALT; AMT; 5-Meo-AMT etc• 126 psychedelic phenethylamines/stimulants from the Shulgin Index (2011); about 1,300 molecules being covered;

including DMAA• GABA-A/GABA-B agonists: 3 GHB-like drugs: GHB; GBL; 1,4-BD; phenibut; baclofen; 50 designer bdz (phenazepam)• PCP-like drugs: PCP; ketamine; methoxetamine; PCE; 3-MeO-PCP; ethylketamine; 3-HO-PCP; diphenidine, MXP etc • piperazines: BZP; TFMPP • Herbs/plants/fungi/animals: Salvia divinorum; Mytragina speciosa/kratom; Tabernanthe iboga/ibogaine; Kava Kava;

Psychotria viridis/Ayahuasca; hydrangea; Magnolia officinalis; Datura stramonium; psychedelic mushrooms; bufo; sponges; flies; etc

• medicinal products: tramadol, oxycodone, and remaining opiates/opiods; anticonvulsants (gabapentin and pregabalin); antiseptics (benzydamine); DXM; venlafaxine/’baby XTC’; bupropion; olanzapine; quetiapine/Qbomb); stimulants (ethylphenidate; camfetamine); antiparkinsonian /anticholinergics: selegiline; tropicamide); chloroquine; anitretrovirals/’whoonga’; xylazine

• IPEDs: minikikke/super strength caffeine tablets; DNP; 3-FPM; clenbuterol; herbal testosterone boosters/Tribulus terrestris; melanotan; sexual enhancers (medicines; herbal products); cognitive enhancers (aniracetam; piracetam; modafinil)

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…the few thousands of different NPS currently available… (part 2)

Diversion of prescription and non-prescription drugs in the context of NPS A growing use of psychoactive pharmaceuticals for recreational

purposes has emerged in the drug scene (Nelson et al., 2014;Schifano et al., 2018). As with them, Over-The-Counter (OTC)medications misuse emerged as a major public health concern(NIDA, 2011).

Misusing prescription drugs and OTCs involves not only risksassociated with drugs, but also:

- side-effects- interactions between drugs (both licensed and unlicensed) and

other substances and products (food/ alcohol)- individual variation in responses (genetic differences and possible

comorbidities) (Benotsch et al., 2014)

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‘Pharming’ phenomenon

• ‘Pharming’ (Levine, 2007): ‘pharm’ parties; ‘trail mix’; ‘chill pill’ (Haller and James, 2010)

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Prescription drug diversion routes (Kurtz et al., 2019)

Diversion of prescription drugsin the context of NPS - II

GABAPENTINOIDS

• Increasing levels of prescriptions

• Rising numbers of emergency rooms visits and related fatalities (Hakkinen et al.,2014; Parsons, 2018)

• High dosages and unusual way of consumption: intravenous; rectal(‘plugging’); smoking; and ‘parachuting’ (emptying the content of thecapsule into a pouch)

• Alone or in combination with other drugs: opiates/opioids may beconcurrently prescribed to potentiate the gabapentinoids’ effects

• Pregabalin is considered an ‘ideal psychotropic drug’ for recreationalpurposes to achieve specific mindsets, including:alcohol/GHB/benzodiazepine-like effects mixed with euphoria; to achieveentactogenic feelings/disassociation; and to cope with opiate/opioidwithdrawal

• ‘Liking and wanting’

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Quetiapine – ‘Susie Q’

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Z-drugs - I

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-Zolpidem-Zaleplon-Zopiclone

Z-drugs - II

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(Griffith and Johnson, 2005)

DESIGNER BENZODIAZEPINES (DBDZ)

• Pharmaceutical drug candidates that have never been approved for medical use(e.g., clonazolam, deschloroetizolam, diclazepam, flubromazepam, and pyrazolam);compounds that were synthesized by a simple structural modification of aregistered drug (e.g., flubromazolam); and some active metabolites of registeredbenzodiazepines (e.g., desmethylflunitrazepam marketed under the name offonazepam) (Zawilska et al., 2019)

• Several DBZD have been placed under national control (ACMD, 2017; UNODC,2017; WHO, 2017)

• Sold on the illicit drug market as counterfeit forms of diazepam and alprazolam,together with fentanyl or synthetic cannabimimetics (Zawilska et al., 2019)

• Toxic effects may last for several days (e.g. phenazepam and flubromazolam), andmay include respiratory depression and death when concomitantly used with otherCNS depressant drugs (Moosmann and Auwärter, 2018)

• Chronic use of DBZD results in the development of tolerance, as well aspsychological and physical dependence

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OTC remedies may beused to achievepsychoactive effects, suchas positive effects andstimulating experiencesand for self-medicationpurposes, such asenhancing studying, painmanagement, improvinghealth, weight loss,relaxation, sleepassistance (Friedman RA, 2006;Quintero et al., 2006; McCabe and Boyd,2012; Schroeder and Ford, 2012; LeClair etal., 2015)

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Their use for non-medicalpurposes may havedeveloped due to theirincreased availability,their inexpensive cost,and the users’perceptions of theirsafety (LeClair et al., 2015; Schroederand Ford, 2012)

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Procured from:- family members-international pharmacies- from the Internet (ratherthan ‘sketchy’ drugdealers)

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The initial genuine use ofthe medication is mostlyreported, howeverintentionalexperimenting suggestedby other users mayhappen

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Usual practice of mixingdifferent OTCs andprescription drugs/otherillicit drugs in order toenhance their effects

Diversion of OTC drugs in the context of NPS

DEXTROMETHORPHAN (DXM)

o DXM is a cough suppressant and opioid derivative

o Since its introduction on the market its abuse emerged,especially among adolescents (Sheridan et al., 2016)

o Dissociative effects through its metabolism by cytochromeCYP2D6 to dextrorphan, an NMDA antagonist. Dextrorphan isalso thought to exert adrenergic effects by inhibiting peripheraland central catecholamine reuptake. Further, DXM has specificserotonergic and sigma-1 opioidergic properties (Miller et al.,2005)

o Toxicity from coformulatory compounds, i.e. hepatotoxic effectsfrom acetaminophen; anticholinergic effects fromdiphenhydramine; depressant effects from ethanol; andsympathomimetic effects from pseudoephedrine

o The abrupt cessation of the drug resulting in physical withdrawalsymptoms (Caffrey and Lank, 2018) 21

STAGE 1(100 -200mg)

STAGE 2(200-400mg)

STAGE 3(300-600mg)

STAGE 4(>600mg)

trance-like euphoria impairment of motor, cognitive, and

perceptual functioning

mild dissociation complete psychophysical dissociation and ‘out of

body’ experiences (‘robo-ing’, ‘robo-copping’, or

‘robo-tripping’)

sense of well-being mild hallucinations feelings of physical distortion

violent behaviours

profound empathy slurred speech anxiety psychotic symptoms, including paranoia, delusional beliefs,

perceptual distortion, and vivid auditory and visual

hallucinations social relaxation lethargy hallucinations possible death

ataxia hyperexcitability

memory impairment poor motor control

Dose-related DXM psychic effects (therapeutic range: from 60 to 120 mg/day in divided doses) (Levine, 2007; Martinek et al., 2017; Miller, 2005; Romanelli and Smith, 2009; Storck et al., 2016).

The “SMART” choice (Miller et al., 2006):

Stigma: there is no negative connotation Money: it is a relatively inexpensive OTC drugAccess: it is OTC and found in many home medicine cabinetsRisks: DXM is available from medical companies Testing: routine drug tests do not test for DXM

CODEINE cough and cold medications22

o Calming effects: being an opioid, it determines rewarding andpleasant effects; relief from tension and anxiety

o Combined with promethazine is popular as ‘purple drank’ or ‘purplelean’, ‘sizzurp’, ‘dirty sprite’, as mixed with soft drinks and candysyrups

o Side effects: dizziness, blurred vision, nausea, memory problems

o Coma and death, especially when codeine is combined with othersedative drugs or depressant substances, such as alcohol

o Chronic use of codeine and ‘purple drank’ can lead to thedevelopment of drug tolerance or dependence

(Chiappini S, Schifano F, Corkery JM, Guirguis A Beyond the 'purpledrank': Study of promethazine abuse according to the EuropeanMedicines Agency adverse drug reaction reports. J Psychopharmacol.2021)

LOPERAMIDE

o It is a peripherally acting opioid derivative used as an OTC antidiarrheal, long considered a drug with low abuse potential

o It has been reported for its euphoric effects (‘lope highs’) and its use to alleviate opiate/opioid withdrawal (‘poors’ methadone’)

o Although safe within normal dosages (2-16mg), at higher dosages (>50mg, up to 800mg) CNS depression, electrocardiogramabnormalities (QTc > 650ms) and fatal cardiotoxicity have been described (Chiappini and Schifano, 2018)

o Some also take advantage of cytochrome inhibitors, such as cimetidine and grapefruit juice, as well as P-GlycoProtein inhibitors, suchas quinidine and pepper, to raise serum levels of the drug

o Loperamide will not show up on a standard urine drug screen

o Management of loperamide toxicity includes extended consideration of decontamination, treatment of respiratory depression, andmonitoring and treatment of potential cardiotoxicity: naloxone has been used for loperamide-provoked respiratory depression(Caffrey and Lank, 2018).

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Other prescription drugs

o Abuse of anticholinergic antiparkinsonian drugs, normally used toameliorate EPS caused by either Parkinson's disease or antipsychotic drugs:Biperidine; Benztropine; Orphenadrine; and Procyclidine (Dose and Tempel,2000; Gjerden et al., 2009; Marken et al., 1996; Reeves et al., 2015)

o Tropicamide is an antimuscarinic drug usually prescribed as an ophthalmicsolution reported to be self-administered IV for recreational purposes(Bersani et al., 2013)

Through the blockade of the muscarinic receptors,anticholinergic drugs inhibit dopamine reuptake andstorage, accounting for the euphoric andhallucinogenic effects (Naja and Halaby, 2017)

3 distinct groups of abusers (Marken et al., 1996) :I. those individuals without valid medical need for

the medication consuming it only for its mind-altering effects;

II. those with a valid indication for the use ofanticholinergics who also abuse them for theirmind-altering effects;

III. those who have an appropriate medical indicationfor the agents and appear to be usinganticholinergics to relieve EPS, depression ornegative schizophrenic symptoms

True abusers couldbe recognisedbecause they feignEPS, repeatedly‘lose’ theirmedications orrequest unnecessarydose increases.

Is medicinal ketamine associated with urinary dysfunction issues? Assessment of both the European Medicines Agency (EMA) and the UK Yellow Card Scheme pharmacovigilance database-related reports (Schifano N, Chiappini S, Schifano F, LUTS 2020)

• Ketamine prescribing is being increasingly considered for psychopathological conditions. A range of ketamine-associated urinary dysfunction (KAUD) issues are typically described in ketamine misusers

• Analysis of both the 2005-2017 European Medicines Agency (EMA) and the 2006-2018 UK Yellow Card Scheme (YCS) pharmacovigilance databases.

• Out of a total of 9,971 ADRs (210 ‘suspect’ single cases), 1,758 ADRs (17.7%; 194 cases) referred to renal/urinary disorders, typically kidney/ureter (922 ADRs) or bladder/urethra (837 ADRs). Ketamine was the sole drug administered in 156/194 (80.4%) cases.

• ADRs occurred in the 1 month-1 year time interval after the start of ketamine administration; in 30 cases the ADR occurred within 48 hours.

• YCS data were consistent with EMA findings, with some 50/217 (23%) ADRs referring to renal/urinary disorders.

• Current datamay only represent a gross underestimate of the KAUD real prevalence issues. Until safety concerns are resolved, it is here suggested that chronic treatment involving higher doses/repeated exposure to ketamine be restricted to the context of controlled trials or clinical audits.

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Milano G, Chiappini S, Mattioli F, Martelli A, Schifano F. beta-2 Agonists as Misusing Drugs? Assessment of both Clenbuterol- and Salbutamol-related European Medicines Agency Pharmacovigilance Database Reports. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):182-187.

• A recent years' increase in misusing levels of image-and performance- enhancing drugs (IPEDs) has been observed.

• Out of these drugs, beta-2 agonists have recently emerged for their potential of misuse, especially for slimming and bodybuilding purposes.

• To this perspective, clenbuterol ('the size zero pill') has been reported as being both popular and widely available from the illegal market

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New/Novel Synthetic Opioids - I

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• Opioid crisis

• Diverted prescription opioid analgesics (e.g., oxycodone,hydrocodone, hydromorphone), failed opioid drug candidates(e.g., benzamide derivatives), and various legal and illegalfentanyl analogues (e.g., acetylfentanyl, furanylfentanyl,carfentanil)

• Low cost of materials and equipment required for clandestinelaboratory production and enormous profit potential

• There is little information available regarding thepharmacology and the toxicology of NSOs in abuse settings

• More than one naloxone dose in case of overdose (up to 12mg)

• Available from the dark web (‘China White’,‘Synthetic Heroin’, ‘Street Oxy’)

• Identified from heroin batches as well (Zawilskaet al., 2017)

New Synthetic Opioids - II

New Synthetic Opioids-III

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Opioids in the NPS Finder:

quantitative and qualitative

analysis

Arillotta D, Schifano F, Napoletano F, Zangani C, Gilgar L, Guirguis A, Corkery JM, Aguglia E, Vento A. Novel Opioids: Systematic Web Crawling Within the e-Psychonauts' Scenario. Front Neurosci. 2020 Mar 18;14:149. doi: 10.3389/fnins.2020.00149.

After a thorough screening, opioids were subdivided into:

•ATC/prescribing opioids (according to WHO): ̴47This list includes 4 fentanyls (alfentanil, fentanyl, remifentanil, sufentanil)

•Herbals: ̴18This list includes opium and poppy straw derivatives, Mitragyna speciosa/kratom, Salvia divinorum/Sally Dand derivatives (salvinorin A and Salvinorin B ethoxymethyl ether)

•Fentanyl analogues: 2̴37 (including ohmefentanyl and carfentanyl derivatives, respectively 6300and 10000 times more powerful than morphine)

•Miscellaneous: ̴134This list includes some morphine derivatives, some precursors and molecules not yet classified elsewhere ornot included above

Further suggestions from the psychonauts’ world (1)

• 6-Methylenedihydrodesoxymorphine: a potent μ-opioid agonist, 80x stronger than morphine.

• BDPC alias Bis(2,4-dinitrophenyl)carbonate or bromadol: studies assigned a value of 504times the potency of morphine for the more active trans-isomer. BDPC/bromadol (Ki = 1.49 nM for MOR)

• Cyclazocine: it is a KOR agonist and MOR partial agonist also having high affinity for the DOR;psychotomimetic, dysphoric, and hallucinatory effects.

• Cyprenorphine: mixed agonist–antagonist effects at opioid receptors, like those of buprenorphine.However the effects are somewhat different, as it produces pronounced dysphoric and hallucinogenic effectswhich limit its potential use as an analgesic.

• O-desmethyltramadol/Krypton: considerably more potent as μ-opioid agonist compared totramadol. It also shows comparatively far lower affinity for the δ- and κ-opioid receptors. It is also anantagonist of the serotonin 5-HT2C receptor, at pharmacologically relevant concentrations, via competitiveinhibition.

• Embutramide: potent opioid analgesic and sedative drug that is structurally related to methadone.Presents with a very narrow therapeutic window; used for euthanasia of a range of different animals; beenreported as being used for suicide by people with access to the drug.

Further suggestions from the psychonauts’ world (2)• Levallorphan: as an agonist of the κ-opioid receptor (KOR), can produce severe mental

reactions.

• Levomethorphan (note dextromethorphan as well): potent agonist of all three of the opioid receptors, μ, κ (κ1 and κ3 but notably not κ2), and δ, as an NMDA receptor antagonist, and as a serotonin-norepinephrine reuptake inhibitor. Can produce dysphoria and psychotomimetic effects such as dissociation and hallucinations.

• Levorphanol: Relative to morphine, lacks complete cross-tolerance and possesses greater intrinsic activity at the MOR and shows a high rate of psychotomimetic side effects such as hallucinations and delusions.

• Nalorphine: an antidote according to ATC classification. Side effects such as dysphoria, anxiety, confusion, and hallucinations, and for this reason, is no longer used medically. It act at the μ-opioid receptor (MOR) where it has antagonistic effects, and at the κ-opioid receptor (KOR) (Ki = 1.6 nM; EC50 = 483 nM; Emax = 95%) where it exerts high-efficacy partial agonist/near-full agonist characteristics.

Remember…. (Schifano, 2020; Psychother Psychosomatics):

• ‘……for most prescription molecules here discussed, including gabapentinoids, one should here emphasize that pre-marketing processes were not able to appropriately identify their misuse and abuse potential

• Pre-authorization trials, however, typically involve the administration of carefully controlled, daily limited, therapeutic dosages, and subjects with a current/previous history of drug misuse are excluded

• Hence, the possible potential of molecules for abuse will be fully appreciated only when the real-world client population, involving vulnerable individuals, is exposed to it……’

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CONCLUSIONS - I

o Non-existence of information on abuse/misuse potential of a medicine interacting with the CNSdoes not mean that a specific medicine does not actually produce these effects

o Healthcare professionals who work in emergency departments, general practice, and mental health/addiction services should beaware of new drug abuse trends, and consider the possible diversion of medicines and the risk of polysubstance abuse

o Education of both clinicians and users is critical in order to identify clinical related-issues, exert special caution with vulnerablecategories, and to treat and prevent the adverse effects and the potential toxicity of OTC and prescription drugs

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